The invention relates to novel strategies for the treatment of resistant cancer patients.
Anti-cancer therapies are frequently ineffective due to resistance of the tumor cells to radio- and/or chemotherapy. When the resistance is acquired during therapy, it often manifests either in a diminished amount of tumor regression for the same dose (either of the radiation or the cytotoxic substance) or an increased dose which is necessary for an equal amount of tumor regression. When, the resistance is intrinsic, i.e. not acquired or induced due to the anti-cancer treatment, the tumor cells already originally lack sensitivity to one or more anti-cancer drugs or ionizing radiation.
The chemosensitivity of cancer cells often vary on an individual basis. For pancreas carcinoma e.g. it is known, that only approximately 25% of all patients benefit from the anti-cancer drug gemcitabine. The other 75% are intrinsically resistant to this chemotherapy. Further examples for tumor cells with intrinsic chemo- and radioresistance are glioblastoma or melanoma cells.
The intrinsic or acquired resistance (or non-response) of tumor cells to radio- and/or chemotherapy can have multiple reasons and can—as exemplified above—vary on an individual basis. Despite intensive research the exact mechanisms still remain elusive. However, it is known that either a single mutation, e.g. at the drug substance binding site or within the cellular detoxification process, can be responsible for the lack of or reduced chemosensitivity. Also the manifestation of cross-resistances to several anticancer drugs often limits the efficacy of anticancer treatments.
Of significant clinical importance is the phenomenon of the so called multi-drug resistance (MDR). According to this concept, membrane proteins, namely members of the ATP binding cassette (ABC) transporter proteins, such as the P-glycoprotein or the multi-drug resistance associated proteins (MRP) are increasingly expressed, which leads to an enhanced efflux of drug substances through active transportation via the cell membrane. Patients exhibiting a multi-drug resistance most often are resistant to a wide spectrum of cytotoxic drugs.
Resistances are not limited to chemotherapeutics or anticancer drugs; cancer patients can also exhibit either an intrinsic or acquired resistance to ionising irradiation applied in radiotherapy. An intrinsic radioresistance is known e.g. from melanoma and glioblastoma cells.
Radioresistance may also be induced by exposure to small or fractionated doses of ionizing radiation. Several studies have documented this effect in vitro even in human cells as well as in several animal models. Different cellular radioprotection mechanisms may be involved, such as alterations in the levels of some cytoplasmatic and nuclear proteins, increased gene expression or DNA repair processes.